The Role of Nitric Oxide in Graft-Versus-Tumor Effect / 대한혈액학회지

ABSTRACT

BACKGROUND: Nitric oxide (NO) synthesis by inducible nitric oxide synthase (iNOS) is induced during graft-versus-host disease (GVHD). It is yet unknown whether NO has any roles in graft-versus-tumor effect (GVT) which is often associated with GVHD. The present study was performed to test the role of NO in GVT. METHODS: GVT was induced by tail vein injection of C57BL/6J (H-2b) mouse splenocytes (10(8)cells/mouse) to [C57BL/6J (H-2(b))XBALB/c (H-2(d))] F1 mice bearing Meth-A (H-2d) ascites tumors. RESULTS: Induction of GVT increased nitrite production (21.0+/-4.1 M) and expression of iNOS protein and mRNA by cells derived from ascites. The increased nitrite production was inhibited by NG-monomethyl-L-arginine (MLA). Immunomagnetic depletion of Mac-1+ cells from ascites cells of GVT mice resulted in a 70% decrease in the nitrite production, indicating that macrophages were implicated as a major cellular source of the nitrite production. Interferon-gamma (IFNgamma) levels in both serum and ascites fluid were markedly increased during GVT. Induction of GVT in ascites tumor-bearing mice prolonged survival from 9.5+/-2.2days to 17.6+/-1.2 days (P<0.001), and increased urinary nitrate excretion up to threefold. MLA administration effectively inhibited the GVT-induced urinary nitrate excretion and further prolonged the GVT-induced increase in survival from 17.6+/-1.2days to 23.6+/-1.9days (P<0.001). CONCLUSION: These results indicate that NO synthesis by iNOS is induced in tumor tissues during GVT, and the NO acts as an inhibitor mechanism of GVT.